A diphenylalanine compound, particularly an optically active diphenylalanine compound (including an amino group-protected compound thereof) is useful as an intermediate for pharmaceutical agents and has been used, for example, as an intermediate for anti-HIV drugs (WO04/056764) or dipeptidyl peptidase inhibitors (WO03/002531).
As a production method of 3,3-diphenylalanine, U.S. Pat. No. 4,766,109 describes, as shown in the following reaction scheme, a method comprising reacting diethyl acetamidomalonate with diphenylbromomethane in ethanol in the presence of sodium ethoxide to give diethyl 2-acetamido-2-(diphenylmethyl)malonate, subjecting the compound to hydrolysis in the presence of hydrogen bromide, neutralizing the reaction mixture with aqueous sodium hydroxide solution, and purifying the compound using a column to give 3,3-diphenylalanine, but the yield thereof is not concretely described.

Thus, the present inventors tried production of 3,3-diphenylalanine by reacting diethyl acetamidomalonate with diphenylchloromethane or diphenylbromomethane according to the above-mentioned reaction scheme. However, diphenylmethyl ethyl ether was mainly obtained as a resultant product, and the objective compound, 3,3-diphenylalanine, could be obtained only in an extremely low yield.
As a different method, a method comprising reacting N-(diphenylmethylene)glycinate, which is synthesized from benzophenoneimine and glycinate, with diphenylbromomethane, as shown in the following reaction scheme, is known (U.S. Pat. No. 5,198,548).

In the above-mentioned method, however, benzophenoneimine, which is a starting material compound, is difficult to obtain, and benzophenoneimine is used only as a leaving group. Therefore, this method is not necessarily considered to be an efficient production method effectively utilizing the starting material compound.
In the meantime, as a production method of optically active diphenylalanine, the aforementioned U.S. Pat. No. 5,198,548 describes a method of optical resolution of N-acetyldiphenylalanine with (−)-cinchonidine. However, this method achieves an inefficient yield of 25-30% in the optical resolution step. In addition, this patent describes a failure in the optical resolution of a 3,3-diphenylalanine compound by hog kidney acylase or carboxypeptidase.
As a still another method, HETEROCYCLES, vol. 57, No. 6, pp. 1143 (2002), and Tetrahedron Letter, vol. 33, No. 23, pp. 3293 (1992) describe asymmetric synthesis of N-Boc-diphenylmethylalanine. However, these methods require stoichiometric amounts of asymmetric sources, many steps, a low temperature reaction vessel to allow reaction at −78° C., and expensive reagents such as KHMDS, (potassium hexamethyldisilazane) and the like, which in turn increases the costs, and therefore, the methods are hardly industrially advantageous methods.
As mentioned above, a production method of an optically active diphenylalanine compound based on a biological technique has not been reported.